Sjögren's syndrome (SS) is a chronic autoimmune disease affecting about 0.5-3% of the given population. SS is primarily characterized by dysfunctional exocrine glands due to lymphocytic infiltration resulting in excessive dry mouth (xerostomia) and dry eyes (keroconjunctivitis Sicca). Autoimmune diseases often share common clinical and pathological features with each other such as an active innate immune response, chronic inflammation, development of specific autoantibodies, systemic dysfunction of multiple organs, etc. SS is most closely associated with the two autoimmune disorders, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Auto-immune diseases are usually more common in females than males. In particular, SS and SLE overwhelmingly affect females to males, with a 9:1 ratio. RA also affects more females than males but less drastically (2-3:1).
Despite overlapping pathophysiological markers shared among SS, SLE and RA patients, the exact mechanism responsible for the onset and progression of these diseases is not fully understood. In recent years, in the search for biomarkers unique to SS or common to SS, SLE and RA several meta-analyses studies have attempted to compare multiple SS gene expression datasets with each other or in conjunction with SLE and RA. In these studies, expression analyses were conducted using peripheral blood mononuclear cells (PBMCs) or biopsies of tissues affected in each disease, i.e., salivary glands in SS, and synovial biopsies in SLE and RA. These meta-analyses studies mostly focused on the identification of genes demonstrating the largest fold changes in mRNA expression in SS patient samples compared to controls. However, large fold changes in transcriptional expression of certain genes observed in these studies could be irrelevant to disease etiology as these may be characteristic of the symptomatology in advanced stages of the disease, rather than disease-onset or pre-symptomatic stages. For example, high levels of type I interferon related genes (e.g., IFN-alpha) are expressed in PBMCs and salivary gland biopsies in SS. However, in salivary glands, increased type I IFN expression could be largely attributed to the frequently observed lymphocytic infiltration and not directly related to etiological mechanisms that would initiate in the salivary glands. Indeed, recently identified potential disease susceptibility genes and infection by viruses with high tropism for exocrine glands are suspected to play an important role in the etiology of SS ahead of the development of systemic autoimmune responses.
Moreover, while SS predominantly occurs in females and an X-chromosome dosage effect has been identified, previous meta-analysis studies comparing SS, SLE, and RA mostly used gene expression data containing both male and female patients. There is a mounting body of evidence suggesting that higher susceptibility to SS in females could be associated with the aberrant expression of specific genes located on the X chromosome in conjunction with X chromosome linked epigenetic events possibly involving the activation of endogenous retroviruses.
In addition, the use of concept profile analysis (CPA) has emerged as a promising approach for biomedical discoveries especially when the amount of data is limited, inadequate or limited categories of controls are used, or there is a lack of general understanding in disease mechanisms. Similar to gene ontology analysis approaches, in CPA each biological entity (e.g., genes, diseases, symptoms, pathways, chemicals, drugs, tissues, toxins . . . etc.) can represent a concept of a concept list (or profile) of another concept and be ranked in order of relevance within the list defining a hierarchy, based on literature mining.
The present invention overcomes previous shortcomings in the art by providing methods and compositions employing epigenetic and gene expression signatures as biomarkers for prediction of risk, progression and response to treatment for exocrine and systemic complications associated with Sjögren's syndrome.